{"gene":"SNX10","run_date":"2026-04-28T20:42:08","timeline":{"discoveries":[{"year":2011,"finding":"SNX10 interacts with the V-ATPase complex and targets it to the centrosome where ciliogenesis is initiated; SNX10 and V-ATPase regulate ciliary trafficking of Rab8a, which is critical for ciliary membrane extension; loss of SNX10 in zebrafish impairs ciliogenesis in Kupffer's vesicle and disrupts left-right patterning.","method":"Loss-of-function assay in cultured cells and zebrafish morpholino knockdown; co-immunoprecipitation; confocal imaging of Rab8a localization","journal":"Cell research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, zebrafish in vivo epistasis, and specific cellular phenotype (cilia loss, Rab8a mislocalization) across multiple orthogonal methods","pmids":["21844891"],"is_preprint":false},{"year":2012,"finding":"SNX10 is required for RANKL-induced osteoclast formation and bone resorption; siRNA-mediated silencing of SNX10 inhibits osteoclast differentiation, TRAP secretion, and resorption on hydroxyapatite; SNX10 localizes to the nucleus and endoplasmic reticulum in osteoclasts.","method":"siRNA knockdown; qPCR; confocal immunofluorescence; subcellular fractionation; hydroxyapatite resorption assay","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 2 — clean KD with defined cellular phenotype, multiple orthogonal methods, and direct localization experiment","pmids":["22174188"],"is_preprint":false},{"year":2012,"finding":"A missense mutation in SNX10 causes autosomal recessive osteopetrosis; mutant SNX10 protein is abnormally abundant and mis-distributed; patient osteoclasts show perturbed endosomal pathway (altered internalized dextran distribution) and markedly impaired resorptive capacity; SNX10 was proposed to sort V-ATPase from Golgi or target it to the ruffled border.","method":"Homozygosity mapping; patient osteoclast functional assays; dextran endocytosis assay; immunofluorescence of mutant protein distribution","journal":"Journal of medical genetics","confidence":"High","confidence_rationale":"Tier 2 — patient-derived osteoclasts with multiple functional readouts, replicated in subsequent studies","pmids":["22499339"],"is_preprint":false},{"year":2013,"finding":"Crystal structure of SNX11 reveals a novel extended phox homology (PXe) domain with two additional C-terminal α-helices; these helices are indispensable for SNX11 function in vitro and the PXe domain is proposed to be present in SNX10, accounting for its vacuolation activity; Tyr32 and Arg51 in SNX10 are important for protein stability and vacuolation activity.","method":"X-ray crystallography of truncated human SNX11; mutagenesis; in vitro vacuolation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure combined with mutagenesis and functional assay","pmids":["23615901"],"is_preprint":false},{"year":2014,"finding":"Crystal structure of human SNX10 at 2.6 Å resolution confirms the extended phox-homology (PXe) domain; structural analysis of disease-related mutations shows Tyr32 and Arg51 are critical for protein stability and vacuolation activity, while Arg16Leu may affect protein-protein interactions relevant to osteoclast function.","method":"X-ray crystallography; mutagenesis; vacuolation activity assay","journal":"Proteins","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with mutagenesis and functional validation","pmids":["25212774"],"is_preprint":false},{"year":2015,"finding":"SNX10 is required for endocytosis, extracellular acidification, ruffled border formation, and bone resorption in osteoclasts; SNX10 is also highly expressed in stomach epithelium where it is required for gastric acidification and calcium solubilization; osteoclast-specific SNX10 knockout causes osteopetrosis without affecting calcium balance, while global knockout causes osteopetrorickets.","method":"Global and osteoclast-specific Snx10 knockout mice; endocytosis assays; extracellular acidification assay; bone histomorphometry; calcium supplementation rescue experiment","journal":"PLoS genetics","confidence":"High","confidence_rationale":"Tier 2 — tissue-specific KO with multiple phenotypic readouts, rescue experiment, replicated across cell types","pmids":["25811986"],"is_preprint":false},{"year":2017,"finding":"SNX10 co-localizes with MMP9 and participates in MMP9 vesicular trafficking; SNX10 knockdown reduces MMP9 secretion and activity while increasing intracellular MMP9 protein; SNX10 overexpression increases MMP9 secretion; SNX10 knockout osteoclasts show downregulated phosphorylation of JNK, p38, and ERK.","method":"siRNA knockdown; co-immunoprecipitation; immunostaining; MMP9 activity assay; western blotting","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — single lab, co-localization and single Co-IP with KD phenotype but limited mechanistic depth","pmids":["28498635"],"is_preprint":false},{"year":2017,"finding":"SNX10 promotes phagosome maturation in macrophages by recruiting the Mon1-Ccz1 complex to endosomes and phagosomes; SNX10 deficiency decreases bacterial killing ability of macrophages and increases susceptibility to Listeria monocytogenes infection in vivo.","method":"SNX10 knockdown/KO macrophages; bacterial killing assay; Mon1-Ccz1 recruitment assay; in vivo infection model","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined cellular phenotype and pathway placement (Mon1-Ccz1 recruitment), single lab","pmids":["28903313"],"is_preprint":false},{"year":2017,"finding":"SNX10 carrying the R51Q mutation (causing ARO in humans) generates dysfunctional osteoclasts with absent ruffled borders and inability to secrete protons, confirmed in a knock-in mouse model exhibiting massive osteopetrosis.","method":"Patient osteoclast functional analysis; splice-site mutation characterization; osteoclast differentiation and resorption assays","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — patient-derived osteoclasts with multiple functional readouts (ruffled border, proton secretion, resorption), replicated across studies","pmids":["28592808"],"is_preprint":false},{"year":2018,"finding":"SNX10 controls chaperone-mediated autophagy (CMA) activity by mediating cathepsin A (CTSA) maturation; SNX10 deficiency inhibits CTSA maturation, increases LAMP-2A stability, and upregulates CMA activity; pull-down assays confirmed direct interaction between SNX10 and CTSA; increased CMA in Snx10 KO mice upregulates Nrf2 and AMPK signaling, alleviating alcohol-induced liver injury.","method":"Snx10 KO mice; pull-down assay (SNX10-CTSA interaction); western blotting for LAMP-2A; LAMP-2A interference; in vitro ethanol treatment; Nrf2/AMPK pathway analysis","journal":"Journal of hepatology","confidence":"High","confidence_rationale":"Tier 2 — KO mice plus pull-down interaction, LAMP-2A interference epistasis, multiple orthogonal methods in one study","pmids":["29452206"],"is_preprint":false},{"year":2019,"finding":"SNX10 controls SRC levels by mediating autophagosome-lysosome fusion and recruiting SRC for autophagic degradation; SNX10 deficiency leads to increased SRC-STAT3 and SRC-CTNNB1 signaling and promotes colorectal cancer progression.","method":"SNX10 KO mice and colorectal epithelial cells; autophagy flux assays; lysosome-autophagosome fusion assay; western blotting for SRC, STAT3, CTNNB1","journal":"Autophagy","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined molecular mechanism (autophagosome-lysosome fusion) and pathway placement, single lab","pmids":["31208298"],"is_preprint":false},{"year":2019,"finding":"SNX10 and PIKfyve colocalize to early endosomes in osteoclasts and co-immunoprecipitate in vesicle fractions; both are required for lysosome formation; PIKfyve inhibitor apilimod requires SNX10 expression for its inhibitory effect on lysosome biogenesis, placing SNX10 upstream of PIKfyve-mediated PI(3,5)P2 synthesis in endosome/lysosome maturation.","method":"Co-immunoprecipitation; subcellular fractionation; apilimod treatment; PIKfyve genetic deletion; confocal co-localization; lysosome formation assay in osteoclasts","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — reciprocal Co-IP with epistasis (apilimod effect requires SNX10), single lab","pmids":["31692073"],"is_preprint":false},{"year":2019,"finding":"FKBP12 was identified as a binding partner of SNX10 in osteoclasts via yeast two-hybrid screening; FKBP12 co-immunoprecipitates with SNX10, co-localizes with SNX10 in osteoclasts, and co-fractionates with SNX10 and EEA1 in early endosome-containing sucrose gradient fractions.","method":"Yeast two-hybrid; co-immunoprecipitation; confocal co-localization; sucrose gradient fractionation","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 3 — yeast two-hybrid plus Co-IP and co-localization, but no functional consequence of the SNX10-FKBP12 interaction tested","pmids":["30887568"],"is_preprint":false},{"year":2020,"finding":"The R51Q SNX10 knock-in mouse model exhibits massive osteopetrosis; mutant osteoclasts lack ruffled borders and cannot secrete protons, confirming R51Q as a causative loss-of-function mutation.","method":"Knock-in mouse model; osteoclast morphology (TEM for ruffled border); proton secretion assay; bone histomorphometry","journal":"Bone","confidence":"High","confidence_rationale":"Tier 2 — knock-in mouse with multiple mechanistic readouts (ruffled border, proton secretion), replicates human disease phenotype","pmids":["32278070"],"is_preprint":false},{"year":2021,"finding":"The R51Q SNX10 mutation causes uncontrolled fusion of mature osteoclasts, forming giant dysfunctional cells; mutant SNX10 protein is unstable and exhibits altered lipid-binding properties; wild-type SNX10 limits osteoclast size by a cell-autonomous mechanism that blocks fusion between mature osteoclasts; mutant OCLs show reduced endocytotic activity, indicating a membrane homeostasis defect.","method":"R51Q SNX10 knock-in mice; time-lapse live imaging of osteoclast fusion; lipid-binding assay; endocytosis assay; protein stability assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 — knock-in mouse model with live imaging, lipid-binding biochemistry, and endocytosis functional assays across multiple orthogonal methods","pmids":["33975343"],"is_preprint":false},{"year":2021,"finding":"SNX10 on early endosomal membranes recruits caspase-5 and PIKfyve in intestinal epithelial cells upon internalization of Gram-negative bacterial outer membrane vesicles (OMVs), leading to LPS release into the cytosol; cytosolic LPS activates caspase-5, which phosphorylates Lyn, promoting nuclear translocation of Snail/Slug, downregulation of E-cadherin, and intestinal barrier dysfunction; SNX10 deletion or inhibition blocks this pathway.","method":"SNX10 KO cells and mice; co-immunoprecipitation/recruitment assays; caspase-5 activation assay; Lyn phosphorylation; E-cadherin/Snail/Slug assays; DSS colitis mouse model","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — KO with defined molecular cascade (OMV→SNX10→caspase-5→Lyn→Snail/Slug→E-cadherin), multiple orthogonal methods, in vivo validation","pmids":["34747049"],"is_preprint":false},{"year":2022,"finding":"NSAIDs upregulate SNX10 via CHOP-dependent ER stress, leading to SNX10-mediated CTSA maturation, lysosomal degradation of LAMP2A, suppression of CMA, and consequent hepatic lipid accumulation (steatosis).","method":"Mouse primary hepatocytes and HepG2 cells; western blotting for LAMP2A and CMA substrates; KFERQ-PAmCherry CMA reporter; LAMP2A overexpression rescue; diclofenac treatment in vivo","journal":"Theranostics","confidence":"Medium","confidence_rationale":"Tier 2 — mechanistic pathway established with reporter assay, rescue experiment, and in vivo model, single lab","pmids":["35265214"],"is_preprint":false},{"year":2024,"finding":"SNX10 directly binds LRP6 and stabilizes it; SNX10 deficiency or disruption of SNX10-LRP6 interaction leads to LRP6 degradation, reduced Wnt/β-catenin signaling, and decreased macrophage apoptosis; gentisic acid binds SNX10 (identified by CETSA/DARTS) and disrupts the SNX10-LRP6 interaction.","method":"CETSA assay; DARTS assay; co-immunoprecipitation (SNX10-LRP6); macrophage-specific SNX10 KO in vivo; western blotting for LRP6 and β-catenin pathway","journal":"Pharmacological research","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with small-molecule target identification (CETSA/DARTS) and in vivo KO, single lab","pmids":["39603572"],"is_preprint":false},{"year":2024,"finding":"SNX10 regulates osteoclast fusion in vivo; SNX10-deficient osteoclasts exhibit persistent DC-STAMP protein at the cell periphery, contributing to uncontrolled fusion; SNX10 KO mice and R51Q knock-in mice both show 2-6-fold larger osteoclast volumes and nuclear numbers in native bone, confirming in vivo deregulated fusion.","method":"SNX10 KO mice; R51Q knock-in mice; EGFP-labeling of osteoclasts; 2-photon/confocal/second harmonic generation microscopy; DC-STAMP immunostaining","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — two independent mouse genetic models with in vivo 3D imaging and molecular marker (DC-STAMP) analysis","pmids":["39095084"],"is_preprint":false},{"year":2025,"finding":"SNX10 is a negative regulator of piecemeal mitophagy; in control conditions SNX10 localizes to early endosomes in a PtdIns3P-dependent manner; under hypoxia-mimicking conditions SNX10 localizes to late endosomal structures containing mitochondrial proteins COX-IV and SAMM50 along with SQSTM1/p62 and LC3B; SNX10 depletion enhances COX-IV turnover, reduces mitochondrial respiration and citrate synthase activity; zebrafish lacking Snx10 show reduced Cox-IV, elevated ROS, and ROS-mediated neuronal death.","method":"SNX10 depletion; live imaging; co-localization of SNX10 with mitochondrial and autophagy markers; mitochondrial respiration assay; citrate synthase activity assay; zebrafish Snx10 KO; ROS measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (imaging, biochemical assays, in vivo zebrafish) with functional consequences, single lab but comprehensive","pmids":["40052924"],"is_preprint":false},{"year":2025,"finding":"SNX10 physically interacts with CLC-7 (the lysosomal Cl-/H+ exchanger); SNX10 is required for trafficking of CLC-7- and OSTM1-containing lysosomes to the cell periphery in osteoclasts; loss of SNX10 reduces peripheral lysosomes, functionally linking SNX10, CLC-7, and OSTM1 in controlling osteoclast fusion arrest and resorptive activity.","method":"Co-immunoprecipitation (SNX10-CLC-7); SNX10 KO osteoclasts; confocal imaging of LAMP1, CLC-7, OSTM1 distribution; comparison of SKO, CLC-7 KO, and OSTM1 KO osteoclast phenotypes","journal":"Journal of bone and mineral research","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP with KO phenotype comparison across three proteins and direct subcellular localization data, moderate evidence","pmids":["41408708"],"is_preprint":false},{"year":2025,"finding":"SNX10 regulates HER2 endosomal trafficking by modulating RAB11A-dependent recycling; SNX10 deficiency attenuates HER2 recycling, promotes HER2 trafficking into lysosomes, decreases cell-surface HER2, and confers resistance to anti-HER2 antibody-drug conjugates in HER2-positive breast cancer.","method":"Transcriptome analysis of patient-derived organoids and resistant cell lines; SNX10 KD/KO; RAB11A assay; HER2 surface expression by flow cytometry; HER2 trafficking assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 — KO with defined trafficking mechanism (RAB11A-dependent recycling), single lab","pmids":["40228127"],"is_preprint":false},{"year":2025,"finding":"SNX10 facilitates phosphorylation of AP2M1 (adaptor protein complex 2 subunit μ1), thereby enhancing clathrin-mediated viral endocytosis of HCoV-OC43; SNX10 also promotes endosomal acidification to facilitate viral genome release; SNX10 KO triggers autophagy activation during infection, promoting lysosomal degradation of virus.","method":"IP-MS (SNX10-AP2M1 interaction); SNX10 KO; viral binding/internalization assays; reconstitution of SNX10 to restore viral entry; endosomal pH measurement; autophagy assay","journal":"Virologica Sinica","confidence":"Medium","confidence_rationale":"Tier 2 — IP-MS interaction plus functional reconstitution and KO phenotype, single lab","pmids":["40645503"],"is_preprint":false},{"year":2025,"finding":"SNX10 interacts with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation, activating mTORC1 and promoting glycolysis; SNX10 knockdown accelerates DEPDC5 degradation; α-hederin binds the SNX10-DEPDC5 complex and impairs their interaction, inhibiting CMA-mediated DEPDC5 degradation and reversing mTORC1 activation.","method":"Co-immunoprecipitation (SNX10-DEPDC5); lysosomal targeting assay; CMA activity assay; mTORC1 pathway western blotting; α-hederin binding assay; SNX10 rescue experiment","journal":"Journal of pharmaceutical analysis","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP with lysosomal recruitment assay and rescue experiment, single lab","pmids":["41487148"],"is_preprint":false},{"year":2025,"finding":"Elevated surface La protein in osteoclasts lacking SNX10 or OSTM1 contributes to pathologic hyperfusion; inhibitory antibodies against La suppress excessive fusion in mutant osteoclasts and restore resorptive function, demonstrating that SNX10 loss leads to aberrant La surface presentation as a molecular mechanism of osteopetrotic hyperfusion.","method":"SNX10 KO and OSTM1 KO murine osteoclasts; La surface expression assay; inhibitory anti-La antibodies; osteoclast fusion assay; resorption assay","journal":"bioRxiv","confidence":"Low","confidence_rationale":"Tier 3 — preprint, single lab, novel finding with antibody rescue but not yet peer-reviewed","pmids":[],"is_preprint":true}],"current_model":"SNX10 is a PX domain-containing endosomal sorting nexin that binds PtdIns3P on early endosomes and regulates multiple vesicular trafficking pathways: it targets V-ATPase to the centrosome/ruffled border to enable osteoclast bone resorption and ciliogenesis; it controls chaperone-mediated autophagy by mediating cathepsin A maturation and LAMP-2A stability; it mediates piecemeal mitophagy by linking endosomal vesicles to mitochondrial proteins; it regulates autophagosome-lysosome fusion for autophagic cargo (e.g., SRC) degradation; it recruits caspase-5 and PIKfyve to endosomes for LPS sensing; it promotes phagosome maturation via Mon1-Ccz1 recruitment; it stabilizes LRP6 and regulates HER2 recycling via RAB11A; it physically interacts with CLC-7 to control lysosome distribution in osteoclasts; and in osteoclasts specifically, SNX10-dependent membrane homeostasis limits fusion between mature cells to maintain proper cell size and resorptive competence."},"narrative":{"teleology":[{"year":2011,"claim":"The discovery that SNX10 interacts with V-ATPase and directs it to the centrosome for ciliogenesis established SNX10 as an active trafficking adaptor rather than a passive endosomal binder, and linked it to ciliary biology and left-right patterning.","evidence":"Co-immunoprecipitation, confocal imaging of Rab8a, and zebrafish morpholino knockdown showing cilia loss in Kupffer's vesicle","pmids":["21844891"],"confidence":"High","gaps":["Whether SNX10-V-ATPase interaction is direct or scaffold-mediated was not resolved","Structural basis of SNX10-V-ATPase recognition unknown"]},{"year":2012,"claim":"Identification of SNX10 loss-of-function mutations in autosomal recessive osteopetrosis (ARO) patients, together with the demonstration that SNX10 knockdown blocks RANKL-induced osteoclast bone resorption, established SNX10 as essential for osteoclast function and linked it to a Mendelian skeletal disease.","evidence":"Homozygosity mapping in ARO families; patient osteoclast resorption and endocytosis assays; siRNA knockdown in cultured osteoclasts with resorption on hydroxyapatite","pmids":["22499339","22174188"],"confidence":"High","gaps":["Precise cargo sorted by SNX10 to the ruffled border was not identified","Whether SNX10 mutations affect osteoclast differentiation or only function was debated"]},{"year":2014,"claim":"Crystal structures of SNX10 (and the closely related SNX11) revealed the extended PXe domain architecture with two additional C-terminal α-helices, and mapped disease mutations (R51Q, Y32, R16L) to stability or interaction surfaces, providing the first structural framework for understanding SNX10 pathophysiology.","evidence":"X-ray crystallography at 2.6 Å; site-directed mutagenesis with vacuolation activity assays","pmids":["25212774","23615901"],"confidence":"High","gaps":["No co-crystal structure with any binding partner","How PXe C-terminal helices mediate protein-protein interactions remained undefined"]},{"year":2015,"claim":"Tissue-specific knockouts resolved that SNX10 functions cell-autonomously in osteoclasts for ruffled border formation and bone resorption, and independently in gastric epithelium for acid secretion and calcium solubilization, explaining the osteopetrorickets phenotype of global knockout.","evidence":"Global and osteoclast-specific Snx10 KO mice with bone histomorphometry, endocytosis and acidification assays, calcium supplementation rescue","pmids":["25811986"],"confidence":"High","gaps":["Molecular identity of cargo sorted by SNX10 in gastric cells not determined","Whether SNX10 delivers V-ATPase or other acidification machinery in stomach was not tested directly"]},{"year":2017,"claim":"Demonstration that SNX10 recruits the Mon1-Ccz1 complex to phagosomes for Rab7 activation and bacterial killing, and that R51Q knock-in mice recapitulate ARO with absent ruffled borders, extended SNX10's role from osteoclasts to innate immune phagosome maturation and validated the disease-causing mechanism in vivo.","evidence":"SNX10 KO macrophages with Mon1-Ccz1 recruitment and Listeria killing assays; R51Q knock-in mouse osteoclast TEM and proton secretion","pmids":["28903313","28592808"],"confidence":"High","gaps":["Whether Mon1-Ccz1 recruitment is a direct SNX10 interaction or indirect was not resolved","Phagosome maturation role not tested outside macrophages"]},{"year":2018,"claim":"The finding that SNX10 directly binds cathepsin A and controls its maturation, thereby regulating LAMP-2A stability and chaperone-mediated autophagy (CMA) activity, revealed a non-classical trafficking function connecting endosomal sorting to selective autophagy.","evidence":"Snx10 KO mice; pull-down assay confirming SNX10-CTSA interaction; LAMP-2A interference epistasis; CMA reporter in hepatocytes","pmids":["29452206"],"confidence":"High","gaps":["Whether SNX10-CTSA interaction occurs on endosomal membranes or in the lumen not established","CMA regulation not confirmed in non-hepatic cell types"]},{"year":2019,"claim":"SNX10 was placed upstream of PIKfyve-dependent PI(3,5)P2 synthesis in endosome-to-lysosome maturation, and shown to control autophagosome-lysosome fusion for SRC degradation, establishing SNX10 as a gatekeeper of lysosome biogenesis and macroautophagy flux.","evidence":"Co-IP of SNX10-PIKfyve with epistasis via apilimod; autophagy flux assays and SRC protein levels in SNX10 KO colorectal cells","pmids":["31692073","31208298"],"confidence":"Medium","gaps":["Direct biochemical mechanism by which SNX10 activates PIKfyve not determined","Whether SRC is a direct autophagy cargo of SNX10-dependent pathway needs confirmation"]},{"year":2021,"claim":"SNX10 was shown to recruit caspase-5 and PIKfyve to early endosomes for LPS sensing from Gram-negative OMVs, establishing an entirely new innate immune signaling axis linking endosomal sorting to non-canonical inflammasome activation and epithelial barrier integrity.","evidence":"SNX10 KO intestinal epithelial cells and mice; co-IP/recruitment of caspase-5; Lyn phosphorylation and Snail/Slug nuclear translocation; DSS colitis model","pmids":["34747049"],"confidence":"High","gaps":["Whether SNX10 directly binds caspase-5 or acts via a scaffold not resolved","Relevance beyond intestinal epithelium not tested"]},{"year":2021,"claim":"Live imaging of R51Q knock-in osteoclasts revealed that SNX10 limits mature osteoclast fusion by a cell-autonomous membrane homeostasis mechanism; loss of SNX10 causes uncontrolled hyperfusion into giant non-resorptive cells, redefining the osteopetrosis defect as a fusion-arrest failure rather than solely a ruffled-border trafficking defect.","evidence":"R51Q knock-in mice; time-lapse live imaging of osteoclast fusion; lipid-binding and endocytosis assays","pmids":["33975343"],"confidence":"High","gaps":["Molecular mechanism connecting SNX10 lipid binding to fusion arrest not identified","Whether hyperfusion alone or combined with trafficking defect causes resorption failure not separated"]},{"year":2024,"claim":"SNX10 was found to stabilize LRP6 (Wnt co-receptor) through direct binding and to control HER2 recycling via RAB11A, broadening SNX10's role to receptor-level regulation of Wnt and RTK signaling with implications for macrophage apoptosis and anti-HER2 drug resistance.","evidence":"CETSA/DARTS for SNX10-LRP6 binding with macrophage-specific KO in vivo; SNX10 KO with RAB11A recycling and HER2 surface expression assays in breast cancer cells","pmids":["39603572","40228127"],"confidence":"Medium","gaps":["Whether SNX10-LRP6 interaction is endosome-dependent not shown","RAB11A regulation mechanism by SNX10 not defined"]},{"year":2025,"claim":"SNX10 was identified as a negative regulator of piecemeal mitophagy, linking endosomal vesicles to mitochondrial proteins under stress; its interaction with CLC-7 was shown to control lysosome peripheral distribution in osteoclasts; and SNX10-dependent DEPDC5 degradation was found to activate mTORC1, revealing new roles in mitochondrial quality control, lysosome positioning, and nutrient signaling.","evidence":"SNX10 KO with mitochondrial respiration and citrate synthase assays plus zebrafish; Co-IP of SNX10-CLC-7 with lysosome distribution imaging in osteoclasts; Co-IP of SNX10-DEPDC5 with CMA and mTORC1 assays","pmids":["40052924","41408708","41487148"],"confidence":"High","gaps":["Whether SNX10-CLC-7 interaction is the primary mechanism of lysosome positioning or one of several parallel pathways","Identity of mitochondrial receptor that links endosomal SNX10 vesicles to mitochondria unknown","DEPDC5 degradation mechanism relies on single-lab Co-IP"]},{"year":null,"claim":"Major unresolved questions include the structural basis of SNX10 interactions with its diverse partners (V-ATPase, CLC-7, CTSA, caspase-5, LRP6, DEPDC5), how a single small PXe-domain protein coordinates so many trafficking pathways, and whether its functions in different cell types reflect shared or distinct molecular mechanisms.","evidence":"","pmids":[],"confidence":"Low","gaps":["No co-crystal structure of SNX10 with any partner","No reconstitution of SNX10 sorting activity in minimal systems","Cell-type-specific interactome not systematically defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[3,4,14,19]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[0,7,9,15,20]}],"localization":[{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[0,7,11,12,15,19]},{"term_id":"GO:0005764","term_label":"lysosome","supporting_discovery_ids":[5,10,11,20,23]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[1]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[0,6,19]}],"pathway":[{"term_id":"R-HSA-9612973","term_label":"Autophagy","supporting_discovery_ids":[9,10,16,19,23]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[0,6,7,11,20,21]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[7,15]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[0,5,11]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[17,23]}],"complexes":[],"partners":["ATP6V1A","CLC-7","CTSA","PIKFYVE","CASP5","LRP6","RAB11A","DEPDC5"],"other_free_text":[]},"mechanistic_narrative":"SNX10 is a PX-domain sorting nexin that functions as a central regulator of endosomal and lysosomal trafficking, controlling vesicle maturation, cargo sorting, and organelle acidification across multiple cell types. Through its PtdIns3P-binding PXe domain, SNX10 localizes to early endosomes where it recruits effectors including V-ATPase, PIKfyve, Mon1-Ccz1, CLC-7, and caspase-5 to direct phagosome maturation, autophagosome-lysosome fusion, chaperone-mediated autophagy via CTSA-dependent LAMP-2A turnover, piecemeal mitophagy, and receptor recycling through RAB11A [PMID:21844891, PMID:29452206, PMID:28903313, PMID:31692073, PMID:40052924, PMID:40228127, PMID:41408708]. In osteoclasts, SNX10 targets V-ATPase and CLC-7/OSTM1-containing lysosomes to the ruffled border, enables proton secretion for bone resorption, and limits mature osteoclast fusion to maintain cell size; loss-of-function mutations including R51Q cause autosomal recessive osteopetrosis characterized by absent ruffled borders, defective acidification, and pathological osteoclast hyperfusion [PMID:22499339, PMID:25811986, PMID:32278070, PMID:39095084]. In epithelial and immune cells, SNX10 recruits caspase-5 to endosomes for cytosolic LPS sensing, stabilizes LRP6 to support Wnt/β-catenin signaling, and regulates HER2 surface expression through RAB11A-dependent recycling [PMID:34747049, PMID:39603572, PMID:40228127]."},"prefetch_data":{"uniprot":{"accession":"Q9Y5X0","full_name":"Sorting nexin-10","aliases":[],"length_aa":201,"mass_kda":23.6,"function":"Probable phosphoinositide-binding protein involved in protein sorting and membrane trafficking in endosomes. Plays a role in cilium biogenesis through regulation of the transport and the localization of proteins to the cilium. Required for the localization to the cilium of V-ATPase subunit ATP6V1D and ATP6V0D1, and RAB8A. Involved in osteoclast differentiation and therefore bone resorption","subcellular_location":"Cytoplasm; Endosome membrane; Cytoplasm, cytoskeleton, microtubule organizing center, centrosome","url":"https://www.uniprot.org/uniprotkb/Q9Y5X0/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SNX10","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/SNX10","total_profiled":1310},"omim":[{"mim_id":"615085","title":"OSTEOPETROSIS, AUTOSOMAL RECESSIVE 8; OPTB8","url":"https://www.omim.org/entry/615085"},{"mim_id":"614780","title":"SORTING NEXIN 10; SNX10","url":"https://www.omim.org/entry/614780"},{"mim_id":"259700","title":"OSTEOPETROSIS, AUTOSOMAL RECESSIVE 1; OPTB1","url":"https://www.omim.org/entry/259700"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Microtubules","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Cytosol","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in 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SNX10 and V-ATPase regulate ciliary trafficking of Rab8a, which is critical for ciliary membrane extension; loss of SNX10 in zebrafish impairs ciliogenesis in Kupffer's vesicle and disrupts left-right patterning.\",\n      \"method\": \"Loss-of-function assay in cultured cells and zebrafish morpholino knockdown; co-immunoprecipitation; confocal imaging of Rab8a localization\",\n      \"journal\": \"Cell research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, zebrafish in vivo epistasis, and specific cellular phenotype (cilia loss, Rab8a mislocalization) across multiple orthogonal methods\",\n      \"pmids\": [\"21844891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SNX10 is required for RANKL-induced osteoclast formation and bone resorption; siRNA-mediated silencing of SNX10 inhibits osteoclast differentiation, TRAP secretion, and resorption on hydroxyapatite; SNX10 localizes to the nucleus and endoplasmic reticulum in osteoclasts.\",\n      \"method\": \"siRNA knockdown; qPCR; confocal immunofluorescence; subcellular fractionation; hydroxyapatite resorption assay\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KD with defined cellular phenotype, multiple orthogonal methods, and direct localization experiment\",\n      \"pmids\": [\"22174188\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"A missense mutation in SNX10 causes autosomal recessive osteopetrosis; mutant SNX10 protein is abnormally abundant and mis-distributed; patient osteoclasts show perturbed endosomal pathway (altered internalized dextran distribution) and markedly impaired resorptive capacity; SNX10 was proposed to sort V-ATPase from Golgi or target it to the ruffled border.\",\n      \"method\": \"Homozygosity mapping; patient osteoclast functional assays; dextran endocytosis assay; immunofluorescence of mutant protein distribution\",\n      \"journal\": \"Journal of medical genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived osteoclasts with multiple functional readouts, replicated in subsequent studies\",\n      \"pmids\": [\"22499339\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Crystal structure of SNX11 reveals a novel extended phox homology (PXe) domain with two additional C-terminal α-helices; these helices are indispensable for SNX11 function in vitro and the PXe domain is proposed to be present in SNX10, accounting for its vacuolation activity; Tyr32 and Arg51 in SNX10 are important for protein stability and vacuolation activity.\",\n      \"method\": \"X-ray crystallography of truncated human SNX11; mutagenesis; in vitro vacuolation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure combined with mutagenesis and functional assay\",\n      \"pmids\": [\"23615901\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Crystal structure of human SNX10 at 2.6 Å resolution confirms the extended phox-homology (PXe) domain; structural analysis of disease-related mutations shows Tyr32 and Arg51 are critical for protein stability and vacuolation activity, while Arg16Leu may affect protein-protein interactions relevant to osteoclast function.\",\n      \"method\": \"X-ray crystallography; mutagenesis; vacuolation activity assay\",\n      \"journal\": \"Proteins\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure with mutagenesis and functional validation\",\n      \"pmids\": [\"25212774\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SNX10 is required for endocytosis, extracellular acidification, ruffled border formation, and bone resorption in osteoclasts; SNX10 is also highly expressed in stomach epithelium where it is required for gastric acidification and calcium solubilization; osteoclast-specific SNX10 knockout causes osteopetrosis without affecting calcium balance, while global knockout causes osteopetrorickets.\",\n      \"method\": \"Global and osteoclast-specific Snx10 knockout mice; endocytosis assays; extracellular acidification assay; bone histomorphometry; calcium supplementation rescue experiment\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tissue-specific KO with multiple phenotypic readouts, rescue experiment, replicated across cell types\",\n      \"pmids\": [\"25811986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX10 co-localizes with MMP9 and participates in MMP9 vesicular trafficking; SNX10 knockdown reduces MMP9 secretion and activity while increasing intracellular MMP9 protein; SNX10 overexpression increases MMP9 secretion; SNX10 knockout osteoclasts show downregulated phosphorylation of JNK, p38, and ERK.\",\n      \"method\": \"siRNA knockdown; co-immunoprecipitation; immunostaining; MMP9 activity assay; western blotting\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single lab, co-localization and single Co-IP with KD phenotype but limited mechanistic depth\",\n      \"pmids\": [\"28498635\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX10 promotes phagosome maturation in macrophages by recruiting the Mon1-Ccz1 complex to endosomes and phagosomes; SNX10 deficiency decreases bacterial killing ability of macrophages and increases susceptibility to Listeria monocytogenes infection in vivo.\",\n      \"method\": \"SNX10 knockdown/KO macrophages; bacterial killing assay; Mon1-Ccz1 recruitment assay; in vivo infection model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined cellular phenotype and pathway placement (Mon1-Ccz1 recruitment), single lab\",\n      \"pmids\": [\"28903313\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SNX10 carrying the R51Q mutation (causing ARO in humans) generates dysfunctional osteoclasts with absent ruffled borders and inability to secrete protons, confirmed in a knock-in mouse model exhibiting massive osteopetrosis.\",\n      \"method\": \"Patient osteoclast functional analysis; splice-site mutation characterization; osteoclast differentiation and resorption assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — patient-derived osteoclasts with multiple functional readouts (ruffled border, proton secretion, resorption), replicated across studies\",\n      \"pmids\": [\"28592808\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SNX10 controls chaperone-mediated autophagy (CMA) activity by mediating cathepsin A (CTSA) maturation; SNX10 deficiency inhibits CTSA maturation, increases LAMP-2A stability, and upregulates CMA activity; pull-down assays confirmed direct interaction between SNX10 and CTSA; increased CMA in Snx10 KO mice upregulates Nrf2 and AMPK signaling, alleviating alcohol-induced liver injury.\",\n      \"method\": \"Snx10 KO mice; pull-down assay (SNX10-CTSA interaction); western blotting for LAMP-2A; LAMP-2A interference; in vitro ethanol treatment; Nrf2/AMPK pathway analysis\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice plus pull-down interaction, LAMP-2A interference epistasis, multiple orthogonal methods in one study\",\n      \"pmids\": [\"29452206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX10 controls SRC levels by mediating autophagosome-lysosome fusion and recruiting SRC for autophagic degradation; SNX10 deficiency leads to increased SRC-STAT3 and SRC-CTNNB1 signaling and promotes colorectal cancer progression.\",\n      \"method\": \"SNX10 KO mice and colorectal epithelial cells; autophagy flux assays; lysosome-autophagosome fusion assay; western blotting for SRC, STAT3, CTNNB1\",\n      \"journal\": \"Autophagy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined molecular mechanism (autophagosome-lysosome fusion) and pathway placement, single lab\",\n      \"pmids\": [\"31208298\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SNX10 and PIKfyve colocalize to early endosomes in osteoclasts and co-immunoprecipitate in vesicle fractions; both are required for lysosome formation; PIKfyve inhibitor apilimod requires SNX10 expression for its inhibitory effect on lysosome biogenesis, placing SNX10 upstream of PIKfyve-mediated PI(3,5)P2 synthesis in endosome/lysosome maturation.\",\n      \"method\": \"Co-immunoprecipitation; subcellular fractionation; apilimod treatment; PIKfyve genetic deletion; confocal co-localization; lysosome formation assay in osteoclasts\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with epistasis (apilimod effect requires SNX10), single lab\",\n      \"pmids\": [\"31692073\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"FKBP12 was identified as a binding partner of SNX10 in osteoclasts via yeast two-hybrid screening; FKBP12 co-immunoprecipitates with SNX10, co-localizes with SNX10 in osteoclasts, and co-fractionates with SNX10 and EEA1 in early endosome-containing sucrose gradient fractions.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation; confocal co-localization; sucrose gradient fractionation\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — yeast two-hybrid plus Co-IP and co-localization, but no functional consequence of the SNX10-FKBP12 interaction tested\",\n      \"pmids\": [\"30887568\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"The R51Q SNX10 knock-in mouse model exhibits massive osteopetrosis; mutant osteoclasts lack ruffled borders and cannot secrete protons, confirming R51Q as a causative loss-of-function mutation.\",\n      \"method\": \"Knock-in mouse model; osteoclast morphology (TEM for ruffled border); proton secretion assay; bone histomorphometry\",\n      \"journal\": \"Bone\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse with multiple mechanistic readouts (ruffled border, proton secretion), replicates human disease phenotype\",\n      \"pmids\": [\"32278070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"The R51Q SNX10 mutation causes uncontrolled fusion of mature osteoclasts, forming giant dysfunctional cells; mutant SNX10 protein is unstable and exhibits altered lipid-binding properties; wild-type SNX10 limits osteoclast size by a cell-autonomous mechanism that blocks fusion between mature osteoclasts; mutant OCLs show reduced endocytotic activity, indicating a membrane homeostasis defect.\",\n      \"method\": \"R51Q SNX10 knock-in mice; time-lapse live imaging of osteoclast fusion; lipid-binding assay; endocytosis assay; protein stability assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — knock-in mouse model with live imaging, lipid-binding biochemistry, and endocytosis functional assays across multiple orthogonal methods\",\n      \"pmids\": [\"33975343\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"SNX10 on early endosomal membranes recruits caspase-5 and PIKfyve in intestinal epithelial cells upon internalization of Gram-negative bacterial outer membrane vesicles (OMVs), leading to LPS release into the cytosol; cytosolic LPS activates caspase-5, which phosphorylates Lyn, promoting nuclear translocation of Snail/Slug, downregulation of E-cadherin, and intestinal barrier dysfunction; SNX10 deletion or inhibition blocks this pathway.\",\n      \"method\": \"SNX10 KO cells and mice; co-immunoprecipitation/recruitment assays; caspase-5 activation assay; Lyn phosphorylation; E-cadherin/Snail/Slug assays; DSS colitis mouse model\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined molecular cascade (OMV→SNX10→caspase-5→Lyn→Snail/Slug→E-cadherin), multiple orthogonal methods, in vivo validation\",\n      \"pmids\": [\"34747049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"NSAIDs upregulate SNX10 via CHOP-dependent ER stress, leading to SNX10-mediated CTSA maturation, lysosomal degradation of LAMP2A, suppression of CMA, and consequent hepatic lipid accumulation (steatosis).\",\n      \"method\": \"Mouse primary hepatocytes and HepG2 cells; western blotting for LAMP2A and CMA substrates; KFERQ-PAmCherry CMA reporter; LAMP2A overexpression rescue; diclofenac treatment in vivo\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic pathway established with reporter assay, rescue experiment, and in vivo model, single lab\",\n      \"pmids\": [\"35265214\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX10 directly binds LRP6 and stabilizes it; SNX10 deficiency or disruption of SNX10-LRP6 interaction leads to LRP6 degradation, reduced Wnt/β-catenin signaling, and decreased macrophage apoptosis; gentisic acid binds SNX10 (identified by CETSA/DARTS) and disrupts the SNX10-LRP6 interaction.\",\n      \"method\": \"CETSA assay; DARTS assay; co-immunoprecipitation (SNX10-LRP6); macrophage-specific SNX10 KO in vivo; western blotting for LRP6 and β-catenin pathway\",\n      \"journal\": \"Pharmacological research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with small-molecule target identification (CETSA/DARTS) and in vivo KO, single lab\",\n      \"pmids\": [\"39603572\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SNX10 regulates osteoclast fusion in vivo; SNX10-deficient osteoclasts exhibit persistent DC-STAMP protein at the cell periphery, contributing to uncontrolled fusion; SNX10 KO mice and R51Q knock-in mice both show 2-6-fold larger osteoclast volumes and nuclear numbers in native bone, confirming in vivo deregulated fusion.\",\n      \"method\": \"SNX10 KO mice; R51Q knock-in mice; EGFP-labeling of osteoclasts; 2-photon/confocal/second harmonic generation microscopy; DC-STAMP immunostaining\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two independent mouse genetic models with in vivo 3D imaging and molecular marker (DC-STAMP) analysis\",\n      \"pmids\": [\"39095084\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 is a negative regulator of piecemeal mitophagy; in control conditions SNX10 localizes to early endosomes in a PtdIns3P-dependent manner; under hypoxia-mimicking conditions SNX10 localizes to late endosomal structures containing mitochondrial proteins COX-IV and SAMM50 along with SQSTM1/p62 and LC3B; SNX10 depletion enhances COX-IV turnover, reduces mitochondrial respiration and citrate synthase activity; zebrafish lacking Snx10 show reduced Cox-IV, elevated ROS, and ROS-mediated neuronal death.\",\n      \"method\": \"SNX10 depletion; live imaging; co-localization of SNX10 with mitochondrial and autophagy markers; mitochondrial respiration assay; citrate synthase activity assay; zebrafish Snx10 KO; ROS measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (imaging, biochemical assays, in vivo zebrafish) with functional consequences, single lab but comprehensive\",\n      \"pmids\": [\"40052924\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 physically interacts with CLC-7 (the lysosomal Cl-/H+ exchanger); SNX10 is required for trafficking of CLC-7- and OSTM1-containing lysosomes to the cell periphery in osteoclasts; loss of SNX10 reduces peripheral lysosomes, functionally linking SNX10, CLC-7, and OSTM1 in controlling osteoclast fusion arrest and resorptive activity.\",\n      \"method\": \"Co-immunoprecipitation (SNX10-CLC-7); SNX10 KO osteoclasts; confocal imaging of LAMP1, CLC-7, OSTM1 distribution; comparison of SKO, CLC-7 KO, and OSTM1 KO osteoclast phenotypes\",\n      \"journal\": \"Journal of bone and mineral research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP with KO phenotype comparison across three proteins and direct subcellular localization data, moderate evidence\",\n      \"pmids\": [\"41408708\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 regulates HER2 endosomal trafficking by modulating RAB11A-dependent recycling; SNX10 deficiency attenuates HER2 recycling, promotes HER2 trafficking into lysosomes, decreases cell-surface HER2, and confers resistance to anti-HER2 antibody-drug conjugates in HER2-positive breast cancer.\",\n      \"method\": \"Transcriptome analysis of patient-derived organoids and resistant cell lines; SNX10 KD/KO; RAB11A assay; HER2 surface expression by flow cytometry; HER2 trafficking assay\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO with defined trafficking mechanism (RAB11A-dependent recycling), single lab\",\n      \"pmids\": [\"40228127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 facilitates phosphorylation of AP2M1 (adaptor protein complex 2 subunit μ1), thereby enhancing clathrin-mediated viral endocytosis of HCoV-OC43; SNX10 also promotes endosomal acidification to facilitate viral genome release; SNX10 KO triggers autophagy activation during infection, promoting lysosomal degradation of virus.\",\n      \"method\": \"IP-MS (SNX10-AP2M1 interaction); SNX10 KO; viral binding/internalization assays; reconstitution of SNX10 to restore viral entry; endosomal pH measurement; autophagy assay\",\n      \"journal\": \"Virologica Sinica\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — IP-MS interaction plus functional reconstitution and KO phenotype, single lab\",\n      \"pmids\": [\"40645503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"SNX10 interacts with DEPDC5 and recruits it to lysosomes for CMA-mediated degradation, activating mTORC1 and promoting glycolysis; SNX10 knockdown accelerates DEPDC5 degradation; α-hederin binds the SNX10-DEPDC5 complex and impairs their interaction, inhibiting CMA-mediated DEPDC5 degradation and reversing mTORC1 activation.\",\n      \"method\": \"Co-immunoprecipitation (SNX10-DEPDC5); lysosomal targeting assay; CMA activity assay; mTORC1 pathway western blotting; α-hederin binding assay; SNX10 rescue experiment\",\n      \"journal\": \"Journal of pharmaceutical analysis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP with lysosomal recruitment assay and rescue experiment, single lab\",\n      \"pmids\": [\"41487148\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Elevated surface La protein in osteoclasts lacking SNX10 or OSTM1 contributes to pathologic hyperfusion; inhibitory antibodies against La suppress excessive fusion in mutant osteoclasts and restore resorptive function, demonstrating that SNX10 loss leads to aberrant La surface presentation as a molecular mechanism of osteopetrotic hyperfusion.\",\n      \"method\": \"SNX10 KO and OSTM1 KO murine osteoclasts; La surface expression assay; inhibitory anti-La antibodies; osteoclast fusion assay; resorption assay\",\n      \"journal\": \"bioRxiv\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — preprint, single lab, novel finding with antibody rescue but not yet peer-reviewed\",\n      \"pmids\": [],\n      \"is_preprint\": true\n    }\n  ],\n  \"current_model\": \"SNX10 is a PX domain-containing endosomal sorting nexin that binds PtdIns3P on early endosomes and regulates multiple vesicular trafficking pathways: it targets V-ATPase to the centrosome/ruffled border to enable osteoclast bone resorption and ciliogenesis; it controls chaperone-mediated autophagy by mediating cathepsin A maturation and LAMP-2A stability; it mediates piecemeal mitophagy by linking endosomal vesicles to mitochondrial proteins; it regulates autophagosome-lysosome fusion for autophagic cargo (e.g., SRC) degradation; it recruits caspase-5 and PIKfyve to endosomes for LPS sensing; it promotes phagosome maturation via Mon1-Ccz1 recruitment; it stabilizes LRP6 and regulates HER2 recycling via RAB11A; it physically interacts with CLC-7 to control lysosome distribution in osteoclasts; and in osteoclasts specifically, SNX10-dependent membrane homeostasis limits fusion between mature cells to maintain proper cell size and resorptive competence.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"SNX10 is a PX-domain sorting nexin that functions as a central regulator of endosomal and lysosomal trafficking, controlling vesicle maturation, cargo sorting, and organelle acidification across multiple cell types. Through its PtdIns3P-binding PXe domain, SNX10 localizes to early endosomes where it recruits effectors including V-ATPase, PIKfyve, Mon1-Ccz1, CLC-7, and caspase-5 to direct phagosome maturation, autophagosome-lysosome fusion, chaperone-mediated autophagy via CTSA-dependent LAMP-2A turnover, piecemeal mitophagy, and receptor recycling through RAB11A [PMID:21844891, PMID:29452206, PMID:28903313, PMID:31692073, PMID:40052924, PMID:40228127, PMID:41408708]. In osteoclasts, SNX10 targets V-ATPase and CLC-7/OSTM1-containing lysosomes to the ruffled border, enables proton secretion for bone resorption, and limits mature osteoclast fusion to maintain cell size; loss-of-function mutations including R51Q cause autosomal recessive osteopetrosis characterized by absent ruffled borders, defective acidification, and pathological osteoclast hyperfusion [PMID:22499339, PMID:25811986, PMID:32278070, PMID:39095084]. In epithelial and immune cells, SNX10 recruits caspase-5 to endosomes for cytosolic LPS sensing, stabilizes LRP6 to support Wnt/β-catenin signaling, and regulates HER2 surface expression through RAB11A-dependent recycling [PMID:34747049, PMID:39603572, PMID:40228127].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"The discovery that SNX10 interacts with V-ATPase and directs it to the centrosome for ciliogenesis established SNX10 as an active trafficking adaptor rather than a passive endosomal binder, and linked it to ciliary biology and left-right patterning.\",\n      \"evidence\": \"Co-immunoprecipitation, confocal imaging of Rab8a, and zebrafish morpholino knockdown showing cilia loss in Kupffer's vesicle\",\n      \"pmids\": [\"21844891\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNX10-V-ATPase interaction is direct or scaffold-mediated was not resolved\", \"Structural basis of SNX10-V-ATPase recognition unknown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Identification of SNX10 loss-of-function mutations in autosomal recessive osteopetrosis (ARO) patients, together with the demonstration that SNX10 knockdown blocks RANKL-induced osteoclast bone resorption, established SNX10 as essential for osteoclast function and linked it to a Mendelian skeletal disease.\",\n      \"evidence\": \"Homozygosity mapping in ARO families; patient osteoclast resorption and endocytosis assays; siRNA knockdown in cultured osteoclasts with resorption on hydroxyapatite\",\n      \"pmids\": [\"22499339\", \"22174188\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise cargo sorted by SNX10 to the ruffled border was not identified\", \"Whether SNX10 mutations affect osteoclast differentiation or only function was debated\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Crystal structures of SNX10 (and the closely related SNX11) revealed the extended PXe domain architecture with two additional C-terminal α-helices, and mapped disease mutations (R51Q, Y32, R16L) to stability or interaction surfaces, providing the first structural framework for understanding SNX10 pathophysiology.\",\n      \"evidence\": \"X-ray crystallography at 2.6 Å; site-directed mutagenesis with vacuolation activity assays\",\n      \"pmids\": [\"25212774\", \"23615901\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No co-crystal structure with any binding partner\", \"How PXe C-terminal helices mediate protein-protein interactions remained undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Tissue-specific knockouts resolved that SNX10 functions cell-autonomously in osteoclasts for ruffled border formation and bone resorption, and independently in gastric epithelium for acid secretion and calcium solubilization, explaining the osteopetrorickets phenotype of global knockout.\",\n      \"evidence\": \"Global and osteoclast-specific Snx10 KO mice with bone histomorphometry, endocytosis and acidification assays, calcium supplementation rescue\",\n      \"pmids\": [\"25811986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular identity of cargo sorted by SNX10 in gastric cells not determined\", \"Whether SNX10 delivers V-ATPase or other acidification machinery in stomach was not tested directly\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Demonstration that SNX10 recruits the Mon1-Ccz1 complex to phagosomes for Rab7 activation and bacterial killing, and that R51Q knock-in mice recapitulate ARO with absent ruffled borders, extended SNX10's role from osteoclasts to innate immune phagosome maturation and validated the disease-causing mechanism in vivo.\",\n      \"evidence\": \"SNX10 KO macrophages with Mon1-Ccz1 recruitment and Listeria killing assays; R51Q knock-in mouse osteoclast TEM and proton secretion\",\n      \"pmids\": [\"28903313\", \"28592808\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Mon1-Ccz1 recruitment is a direct SNX10 interaction or indirect was not resolved\", \"Phagosome maturation role not tested outside macrophages\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"The finding that SNX10 directly binds cathepsin A and controls its maturation, thereby regulating LAMP-2A stability and chaperone-mediated autophagy (CMA) activity, revealed a non-classical trafficking function connecting endosomal sorting to selective autophagy.\",\n      \"evidence\": \"Snx10 KO mice; pull-down assay confirming SNX10-CTSA interaction; LAMP-2A interference epistasis; CMA reporter in hepatocytes\",\n      \"pmids\": [\"29452206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNX10-CTSA interaction occurs on endosomal membranes or in the lumen not established\", \"CMA regulation not confirmed in non-hepatic cell types\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"SNX10 was placed upstream of PIKfyve-dependent PI(3,5)P2 synthesis in endosome-to-lysosome maturation, and shown to control autophagosome-lysosome fusion for SRC degradation, establishing SNX10 as a gatekeeper of lysosome biogenesis and macroautophagy flux.\",\n      \"evidence\": \"Co-IP of SNX10-PIKfyve with epistasis via apilimod; autophagy flux assays and SRC protein levels in SNX10 KO colorectal cells\",\n      \"pmids\": [\"31692073\", \"31208298\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct biochemical mechanism by which SNX10 activates PIKfyve not determined\", \"Whether SRC is a direct autophagy cargo of SNX10-dependent pathway needs confirmation\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"SNX10 was shown to recruit caspase-5 and PIKfyve to early endosomes for LPS sensing from Gram-negative OMVs, establishing an entirely new innate immune signaling axis linking endosomal sorting to non-canonical inflammasome activation and epithelial barrier integrity.\",\n      \"evidence\": \"SNX10 KO intestinal epithelial cells and mice; co-IP/recruitment of caspase-5; Lyn phosphorylation and Snail/Slug nuclear translocation; DSS colitis model\",\n      \"pmids\": [\"34747049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNX10 directly binds caspase-5 or acts via a scaffold not resolved\", \"Relevance beyond intestinal epithelium not tested\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Live imaging of R51Q knock-in osteoclasts revealed that SNX10 limits mature osteoclast fusion by a cell-autonomous membrane homeostasis mechanism; loss of SNX10 causes uncontrolled hyperfusion into giant non-resorptive cells, redefining the osteopetrosis defect as a fusion-arrest failure rather than solely a ruffled-border trafficking defect.\",\n      \"evidence\": \"R51Q knock-in mice; time-lapse live imaging of osteoclast fusion; lipid-binding and endocytosis assays\",\n      \"pmids\": [\"33975343\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular mechanism connecting SNX10 lipid binding to fusion arrest not identified\", \"Whether hyperfusion alone or combined with trafficking defect causes resorption failure not separated\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"SNX10 was found to stabilize LRP6 (Wnt co-receptor) through direct binding and to control HER2 recycling via RAB11A, broadening SNX10's role to receptor-level regulation of Wnt and RTK signaling with implications for macrophage apoptosis and anti-HER2 drug resistance.\",\n      \"evidence\": \"CETSA/DARTS for SNX10-LRP6 binding with macrophage-specific KO in vivo; SNX10 KO with RAB11A recycling and HER2 surface expression assays in breast cancer cells\",\n      \"pmids\": [\"39603572\", \"40228127\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether SNX10-LRP6 interaction is endosome-dependent not shown\", \"RAB11A regulation mechanism by SNX10 not defined\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"SNX10 was identified as a negative regulator of piecemeal mitophagy, linking endosomal vesicles to mitochondrial proteins under stress; its interaction with CLC-7 was shown to control lysosome peripheral distribution in osteoclasts; and SNX10-dependent DEPDC5 degradation was found to activate mTORC1, revealing new roles in mitochondrial quality control, lysosome positioning, and nutrient signaling.\",\n      \"evidence\": \"SNX10 KO with mitochondrial respiration and citrate synthase assays plus zebrafish; Co-IP of SNX10-CLC-7 with lysosome distribution imaging in osteoclasts; Co-IP of SNX10-DEPDC5 with CMA and mTORC1 assays\",\n      \"pmids\": [\"40052924\", \"41408708\", \"41487148\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SNX10-CLC-7 interaction is the primary mechanism of lysosome positioning or one of several parallel pathways\", \"Identity of mitochondrial receptor that links endosomal SNX10 vesicles to mitochondria unknown\", \"DEPDC5 degradation mechanism relies on single-lab Co-IP\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Major unresolved questions include the structural basis of SNX10 interactions with its diverse partners (V-ATPase, CLC-7, CTSA, caspase-5, LRP6, DEPDC5), how a single small PXe-domain protein coordinates so many trafficking pathways, and whether its functions in different cell types reflect shared or distinct molecular mechanisms.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No co-crystal structure of SNX10 with any partner\", \"No reconstitution of SNX10 sorting activity in minimal systems\", \"Cell-type-specific interactome not systematically defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [3, 4, 14, 19]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [0, 7, 9, 15, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [0, 7, 11, 12, 15, 19]},\n      {\"term_id\": \"GO:0005764\", \"supporting_discovery_ids\": [5, 10, 11, 20, 23]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [0, 6, 19]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-9612973\", \"supporting_discovery_ids\": [9, 10, 16, 19, 23]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [0, 6, 7, 11, 20, 21]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [7, 15]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [0, 5, 11]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [17, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ATP6V1A\",\n      \"CLC-7\",\n      \"CTSA\",\n      \"PIKfyve\",\n      \"CASP5\",\n      \"LRP6\",\n      \"RAB11A\",\n      \"DEPDC5\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}